Process for preparing N6-substituted adenosine derivatives

Abstract

This invention is directed to a process for preparing N6-substituted adenosine derivatives, to intermediates useful therefor and to methods of preparing these intermediates.

What is claimed is:  
     
       1. A process for preparing an N-protected N6-substituted adenosine isostere of formula                    
       wherein 
       P is a nitrogen protecting group;  
       Q is CH 2 ;  
       T is                    
        or R 3 O—CH 2 ;  
       X is a straight or branched chain alkylene, cycloalkylene or cycloalkenylene group;  
       Y is NR 4 , O or S;  
       a=0 or 1;  
       Z is of the formula                    
       Z 1  is N, CR 5 , (CH) m —CR 5  or (CH) m —N, m being 1 or 2;  
       Z 2  is N, NR 6 , O or S;  
       n is 0 or 1;  
       R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are independently H, alkyl, aryl or heterocyclyl;  
       R 7  and R 8  are independently H, alkyl, aralkyl, carbamoyl, alkyl carbamoyl, dialkylcarbamoyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, or R 7  and R 8  together may form                    
        where R c  is hydrogen or alkyl,                    
        where R d  and R e  are independently hydrogen, alkyl, or R d  and R e  together with the carbon atom to which they are attached may form a cycloalkyl group; and  
       R a  and R b  are independently H, OH, alkyl, hydroxyalkyl, alkyl mercaptyl, thioalkyl, alkoxy, alkyoxyalkyl, amino, alkyl amino, carboxyl, acyl, halogen, carbamoyl, alkyl carbamoyl, aryl or heterocyclyl, said process comprising reacting a 4-N-protected-2,3,4-triaminopyridine compound of formula                    
       with a formic acid derivative,  
       where heterocyclyl is about a 4 to about a 10 membered ring structure in which one or more of the atoms in the ring is N, O or S, and which may be aromatic or non-aromatic. 
     
     
       2. The process of  claim 1  wherein P is selected from the group consisting of methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-methoxybenzenesulfonyl, phenacylsulfonyl, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl, tert-butoxycarbonyl, formyl, acetyl, benzoyl, trifluoroacetyl, benzyl and diphenylphosphinoyl. 
     
     
       3. The process of  claim 1  wherein P is selected from the group consisting of methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-methoxybenzenesulfonyl and phenacylsulfonyl. 
     
     
       4. The process of  claim 3  wherein 
       Q is CH 2 ;  
       T is                    
       X is a straight or branched chain alkylene;  
       a=0,  
       Z is                    
       Z 1  is N, CR 5 , (CH) m —CR 5  or (CH) m —N, m being 1 or 2;  
       Z 2  is N, NR 6 , O or S;  
       n is 0 or 1;  
       R 1 , R 2 , R 5  and R 6  are independently H or alkyl;  
       R 7  and R 8  are alkyl, or R 7  and R 8  together may form                    
        where R d  and R e  are independently hydrogen or alkyl, or together with the carbon atom to which they are attached may form a 1,1-cycloalkyl group; and  
       R a  and R b  are independently H, OH, alkyl, hydroxyalkyl, alkyl mercaptyl, thioalkyl, alkoxy, alkyoxyalkyl, amino, alkyl amino, carboxyl, acyl, halogen, carbamoyl, alkyl carbamoyl, aryl or heterocyclyl.  
     
     
       5. The process of  claim 1  further comprising removing the nitrogen protecting group P. 
     
     
       6. The process of  claim 1  further comprising reducing a 4-N-protected 3-nitro-2,4-diaminopyridine compound of formula                    
       to form the 4N-protected-2,3,4-triaminopyridine compound of formula                    
     
     
       7. The process of  claim 6  further comprising reacting an N-protected amino compound of formula P—NH—X—(Y) a —Z with a 2,4-dihalo-3-nitropyridine compound of formula                    
       wherein X 1  and X 2  are independently Cl or F to form a 2-halo-3-nitro-4-N-protected aminopyridine compound of formula                    
     
     
       8. The process of  claim 1  wherein the 4-N-protected 2,3,4-triaminopyridine compound is [3aR-[3aα,4α,6a(R*),6aα]]-6-[4-[[1-[(3-chlorothiein-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide. 
     
     
       9. The process of  claim 6  wherein the 4-N-protected 3-nitro-2,4-diaminopyridine compound is [3aR-(3aα, 4α,6a(R*),6aα]]-6-[4[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide. 
     
     
       10. The process of  claim 7  wherein the N-protected amino compound of formula —-NH—X—(Y) a —Z is (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzenesulfonamide or (R)—N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzenesulfonamide lithium salt. 
     
     
       11. A process according to  claim 1  for preparing [3aR-[3aα,4α,6a (R*),6aα]]-6-[7-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino-3H-imidazo[4,5-b]pyrid-3-yl]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide comprising 
       (i) reacting (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-fluoro-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide with 3aR-[3aR-[3aα,4α,6a,6aα]-6-amino-N-ethyltetrahydro-3,3 -dimethyl-2,4-dioxabicyclo [3,3,0]octan-8-carboxamide, benzoate to form [3aR-[3aα,4α,6a(R*),6aα]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-nitropyrid-2-ylamino]N-ethyl tetrahydron-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide,  
       (ii) reducing the [3aR-[3aα, 4α,6a(R*),6aα]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]aminio-3-nitropyrid-2-ylamino]N-ethyl tetrahydro-2,2-diminethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide prepared in step (i) to form [3aR-[3aα4α,6a(R*),6aα]]-6-[[1-[3-clorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide and  
       (iii) reacting the [3aR-[3aα,4α,6a(R*),6aα]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide prepared in step 2 above with an orthoformate ester, formamidine acetate or dimethylformamide dimethyl acetal,  
       wherein steps (i)-(iii) are performed in a concatenated fashion without purification of the intermediate compounds [3aR-[3aα,4α,6a(R*),6aα]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-nitropyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-1-4H-cyclopenta-1,3-dioxole-4-carboxamide and [3aR-[3aα,4α,6a(R*),6aα]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide. 
     
     
       12. A process for preparing (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-fluoro-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide comprising 
       (i) reacting 2,4-dichloro-3-nitropyridine with a fluorinating agent to form 2,4-difluoro-3-nitropyridine and  
       (ii) reacting the product of step (i) with (R)-N-[1-[(3-chlorothien-2-yl )methylpropyl]-4-methylbenzensulfonamide lithium salt or (R)-N-[1-[(3-clorothien-2-yl)methyl]propyl]-4-methylbenzenesulfonamide, wherein steps (i) and (ii) are performed in a concatenated fashion without isolation of the product of step (i).  
     
     
       13. A process according to  claim 1  for preparing [3aR-[3aα,4α, 6a(R*),6aα]]-6-[7-[[1-[3-chlorothien-2-yl) methyl]propyl][4-methylbenzenesulfonyl]amino]-3H-imidazo[4,5-b]pyrid-3-yl]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide comprising 
       (i) reacting 2,4-dichloro-3-nitropyridine with a fluorinating agent to form 2,4-difluoro-3-nitropyridine,  
       (ii) reacting the 2,4-difluoro-3-nitropyridine with (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzenesulfonamide lithium salt or (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzenesulfonamide to form (R)-N-[1-[3 -chlorothien-2-yl)methyl]propyl]-N-(2-fluoro-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide,  
       (iii) reacting the (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-fluoro-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide with 3aR-[3aα,4α,6a,6aα]-6-amino-N-ethyltetrahydro-3,3-dimethyl-2,4-dioxabicyclo[3,3,0]octan-8-carboxamide, benzoate to form [3aR-[3aα,4a,6a(R*),6aα]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-nitropyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide,  
       (iv) reducing the [3aR-[3aα,4α,6a(R*),6aα]]-6-[-4-[[1-[(3-chlorothien-2-yl)methyl]benzenesulfonyl]amino]-3-nitropyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide prepared in step (iii) to form [3aR-[3aα,4α,6a(R*),6aα]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide and  
       (v) reacting the [3aR-[3aα,4α,6a(R*),6a α]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide with an orthoformate ester, formamidine acetate or dimethylformamide dimethyl acetal, wherein steps (i)-(v) are performed in a concatenated fashion without purification of the intermediate compounds 2,4-dilfuoro-3-nitropyridine, (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-halo-3nitropyrid-4-yl)-4-methylbenzenesulfonamide, [3aR-[3aα,4α,6a(R*),6aα]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenlzenesulfonyl]amino]-3-nitropyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide and [3aR-[3aα,4α,6a(R*),6aα]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopeta-1,3-dioxole-4-carboxamide.  
     
     
       14. A compound of formula                    
       wherein 
       A is NH 2  or NO 2 ;  
       P is a nitrogen protecting group;  
       W is Cl, F or a group of formula                    
       Q is CH 2 ;  
       T is                    
        or R 3 O—CH 2 ;  
       X is a straight or branched chain alkylene, cycloalkylene or cycloalkenylene group;  
       Y is NR 4 , O or S;  
       a=0 or 1;  
       Z is of the formula                    
       Z 1  is N, CR 5 , (CH) m —CR   5  or (CH) m —N, m being 1 or 2;  
       Z 2 is N, NR 6 , O or S;  
       n is 0 or 1;  
       R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are independently H, alkyl, aryl or heterocyclyl;  
       R 7  and R 8  are independently H, alkyl, aralkyl, carbamoyl, alkyl carbamoyl, dialkylcarbamoyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, or aryloxycarbonyl, or R 7  and R 8  together may form                    
        where R c  is hydrogen or alkyl,                    
        where R d  and R e  are independently hydrogen, or alkyl, or R d  and R e  together with the carbon atom to which they are attached may form a cycloalkyl group; and  
       R a  and R b  are independently H, OH, alkyl, hydroxyalkyl, alkyl mercaptyl, thioalkyl, alkoxy, alkyoxyalkyl, amino, alkyl amino, carboxyl, acyl, halogen, carbamoyl, alkyl carbamoyl, aryl or heterocyclyl,  
       where heterocyclyl is about a 4 to about a 10 membered ring structure in which one or more of the atoms in the ring is N, O or S, and which may be aromatic or non-aromatic. 
     
     
       15. The compound of  claim 14  wherein P is selected from the group consisting of methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-methoxybenzenesulfonyl, phenacylsulfonyl, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl, tert-butoxycarbonyl, formyl, acetyl, benzoyl, trifluoroacetyl, benzyl and diphenylphosphinoyl. 
     
     
       16. The compound of  claim 14  wherein P is selected from the group consisting of methanesulfonyl, trifluorobmethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-methoxybenzenesulfonyl and phenacylsulfonyl. 
     
     
       17. The compound of  claim 16  wherein 
       Q is CH 2 ;  
       T is                    
       X is a straight or branched chain alkylene;  
       a=0;  
       Z is                    
       Z 1  is N, CR 5 , (CH) m —CR 5  or (CH) m —N, m being 1 or 2;  
       Z 2  is N, NR 6 , O or S, n being 0 or 1;  
       R 1 , R 2 , R 5  and R 6  are independently H or alkyl;  
       R 7  and R 8  are alkyl, or R 7  and R 8  together may form                    
        where R d  and R e  are independently hydrogen or alkyl, or together with the carbon atom to which they are attached may form a cycloalkyl group; and  
       R a  and R b  are independently H, OH, alkyl, hydroxyalkyl, alkyl mercaptyl, thioalkyl, alkoxy, alkyoxyalkyl, amino, alkyl amino, carboxyl, acyl, halogen, carbamoyl, alkyl carbamoyl, aryl or heterocyclyl.  
     
     
       18. A compound of  claim 14  selected from 
       [3aR-[3aα,4α,6a(R*),6aα]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide;  
       [3aR-[3aα,4α,6a(R*),6aα]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide; and  
       [3aR-[3aα,4α,6a(R*),6aα]]-6-[7-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3H-imidazo[4,5-b]pyrid-3-yl]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide.